ARP, the cleavable C-terminal peptide of "readthrough" acetylcholinesterase, promotes neuronal development and plasticity

Amir Dori, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

Abstract

The mammalian acetylcholinesterase (ACHE) gene gives rise to diverse enzymatically active proteins with three different carboxyl termini. In the brain, the normally rare readthrough AChE-R monomer accumulates under embryonic development and in adults following psychological stress, head injury, or exposure to AChEs. In the prenatal developing cortex, its unique C-terminal peptide ARP associates with radial glial fibers supporting neuronal migration. In contrast, the major synaptic AChE-S variant appears in the migrating neurons themselves. Moreover, antisense suppression of AChE-R attenuates neuronal migration, allowing increased proliferation of neuronal progenitors. In the adult brain, neuronal AChE-R is either secreted or accumulates intraneuronally, where it interacts through ARP with the scaffold protein RACK1 and activated PKC-βII. This associates with increased PKC-βII activity, which shuttles to submembranal clusters (e.g., in hyperactivated hippocampal neurons). Cleavage yields the AChE-R-specific C-terminal peptide, including immunopositive ARP. Importantly, intrahippocampal injection of synthetic ARP was followed by its efficient neuronal penetration and retrograde transport into cortical and basal nuclei neurons. Moreover, ARP-injected mice presented increased stress-induced contextual fear, inhibitable by antisense suppression of AChE-R mRNA. Together, our findings point at the cleavable ARP peptide as a key regulator of neuronal development and plasticity and suggest its use as a drug target and/or research and therapeutic tool.

Original languageEnglish
Pages (from-to)247-255
Number of pages9
JournalJournal of Molecular Neuroscience
Volume28
Issue number3
DOIs
StatePublished - 2006
Externally publishedYes

Keywords

  • Alternative splicing
  • Neurogenesis
  • Radial glia
  • Readthrough acetylcholinesterase
  • Stress response

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